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© 2001 American Society for Clinical Oncology Long-Term Results of Combined-Modality Therapy for Locally Advanced Breast Cancer With Ipsilateral Supraclavicular Metastases: The University of Texas M.D. Anderson Cancer Center ExperienceFrom the Departments of Breast Medical Oncology, Surgical Oncology, and Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Vicente Valero, MD, Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Box 56, 1515 Holcombe Blvd, Houston, TX 77030; email: vvalero{at}mdanderson.org
PURPOSE: To determine outcomes in local-regional control, disease-free survival, and overall survival in patients with locally advanced breast cancer (LABC) who present with ipsilateral supraclavicular metastases and who are treated with combined-modality therapy. PATIENTS AND METHODS: Seventy patients with regional stage IV LABC, which is defined by our institution as LABC with ipsilateral supraclavicular adenopathy without evidence of distant disease, received treatment on three prospective trials of neoadjuvant chemotherapy. All patients received neoadjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil, or cyclophosphamide, doxorubicin, vincristine, and prednisone. Patients then received local therapy that consisted of either total mastectomy and axillary lymph node dissection (ALND) or segmental mastectomy and ALND before or after irradiation. Patients with no response to neoadjuvant chemotherapy were treated with surgery and/or radiotherapy. After completion of local therapy, chemotherapy was continued for four to 15 cycles, followed by radiotherapy. Patients older than 50 years who had estrogen receptor–positive tumors received tamoxifen for 5 years. RESULTS: Median follow-up was 11.6 years (range, 4.8 to 22.6 years). Disease-free survival rates at 5 and 10 years were 34% and 32%, respectively. The median disease-free survival was 1.9 years. Overall survival rates at 5 and 10 years were 41% and 31%, respectively. The median overall survival was 3.5 years. The overall response rate (partial and complete responses) to induction chemotherapy was 89%. No treatment-related deaths occurred. CONCLUSION: Patients with ipsilateral supraclavicular metastases but no other evidence of distant metastases warrant therapy administered with curative intent, ie, combined-modality therapy consisting of chemotherapy, surgery, and radiotherapy. Patients with ipsilateral supraclavicular metastases should be included in the stage IIIB category of the tumor-node-metastasis classification because their clinical course and prognosis are similar to those of patients with stage IIIB LABC.
LOCALLY ADVANCED breast cancer (LABC) is the term used to describe a heterogeneous collection of breast neoplasms. Tumors in all of the following stage categories of the American Joint Committee on Cancer (AJCC) staging and end results reporting system (the so-called tumor-node-metastasis classification)1,2 are considered LABC: IIB (T3 N0 M0), IIIA (T3 N1/2 M0, any T N2 M0), IIIB (T4 any N M0, any T N3 M0) or regional IV (any T any N M1). "Regional stage IV LABC" is used by our institution to describe breast cancer with ipsilateral supraclavicular adenopathy without evidence of distant disease. Currently, patients with regional stage IV LABC are included in the stage IV (distant metastases) category of the tumor-node-metastasis classification. Before 1988, these patients were classified in the stage IIIB category. Ipsilateral supraclavicular metastases from breast cancer are considered an ominous sign. They represent a late stage of regional metastases, and despite aggressive local and regional treatment, cure is rare. Most patients develop distant metastases within 1 year of detection of supraclavicular lymph node involvement.3 Radiotherapy alone or in combination with surgical resection was the previous standard of care. Although high local control rates were observed with this treatment strategy, survival for patients treated only with local therapy was dismal.4 Since the early 1970s, physicians at The University of Texas M.D. Anderson Cancer Center have used a combined-modality approach to treat patients with LABC, including patients with regional stage IV disease. The results of these studies have been published at various follow-up intervals and have demonstrated that patients with LABC can experience long-term disease-free and overall survival if they are treated with the combination of neoadjuvant primary chemotherapy, surgery, radiotherapy, and adjuvant chemotherapy.5-8 We reviewed our experience with such combined-modality therapy to determine the results of this treatment in local control, long-term disease-free survival, and overall survival in the subset of patients with supraclavicular lymph node involvement at presentation.
Patients We reviewed the records of all 598 patients with LABC who were treated on three prospective trials of combined-modality therapy for LABC at M.D. Anderson Cancer Center between 1974 and 1991. Results of these trials have been updated through May 1999. We identified 70 patients who presented with ipsilateral supraclavicular metastases but no evidence of other distant metastases. Before chemotherapy, each patient underwent a staging work-up that consisted of a clinical history, physical examination, bilateral mammography, chest roentgenography, nuclear bone scan, nuclear liver scan (in more recent years, computed tomography or sonography of the liver, or both), and biopsies of the breast to document invasive disease. Patients with distant metastases other than ipsilateral supraclavicular metastases were excluded. In accordance with institutional policy, written consent was obtained from each patient after the research study was explained. Each patient was evaluated in a multidisciplinary planning clinic before therapy was initiated. The clinical team consisted of a radiation oncologist, a surgical oncologist, and a medical oncologist and was supported by a breast radiologist.
Treatment Plan
In the second study, which was initiated in 1985 and for which accrual was completed in 1989, the role of alternate noncross-resistant drugs was evaluated. The treatment schema and details of the chemotherapy regimen are shown in Fig 2. For their initial therapy, patients received a combination of vincristine, prednisone, doxorubicin, and cyclophosphamide (VACP), which was administered in escalating doses to tolerance. After completion of three cycles of chemotherapy, patients with objective responses underwent surgery. If the pathologic specimen had no tumor or if the amount of residual disease was less than 1 cm3, patients received five more cycles of VACP. Patients with objective responses but with an amount of residual disease greater than or equal to 1 cm3 were randomly assigned to receive five more cycles of VACP or five cycles of an alternate noncross-resistant regimen of vinblastine, methotrexate, fluorouracil and folinic acid. After completion of all chemotherapy, patients received radiotherapy. Patients with a minimal response or no response to the first three cycles of chemotherapy were treated with five cycles of vinblastine, methotrexate, fluorouracil, and folinic acid after completion of surgical therapy.
In the third study ( Fig 3), which was initiated in 1989 and completed in 1991, the feasibility of breast conservation was evaluated prospectively. All patients received FAC at the same doses and on a similar schedule as in the initial study with two exceptions: doxorubicin was administered as a continuous infusion during a 72-hour period to reduce the risk of cardiac dysfunction, and local therapy was offered after four cycles of FAC instead of after three cycles. At the conclusion of all therapy, patients older than 50 years who had estrogen receptor–positive tumors received tamoxifen for 5 years.
Patient Follow-Up During the first 2 years of follow-up, patients underwent history and physical examinations, complete blood counts, and liver function tests every 4 months. Any abnormalities in liver function tests were followed up with sonography, computed tomography, or a bone scan as warranted. A chest x-ray was obtained every 6 months. Mammograms of the contralateral breast and, in the case of breast conservation therapy, mammograms of the treated breast were obtained every 6 months. After 2 years, these studies were performed at yearly intervals.
Data Analysis
Patient Characteristics Patient characteristics are listed in Table 1. The median follow-up time from the initiation of therapy was 11.6 years (range, 4.8 to 22.6 years). The median patient age was 49 years (range, 24 to 78 years). Estrogen receptor status was available in 39 patients. Progesterone receptor assays were performed seldom during the early trials, so progesterone receptor status was known in only 11 patients. Forty-five patients were treated on the first protocol, 13 on the second, and 12 on the third.
Response Rates Response rates are listed in Table 2. The overall response rate (complete response plus partial response) to neoadjuvant chemotherapy was 89%. Twenty-one percent of the patients experienced clinical complete response, 67% had a partial response, 6% had a minimal response, and 4% had no change; 1% of patients experienced disease progression during chemotherapy.
Local-Regional Control Local-regional failure was defined as recurrence in the ipsilateral chest wall, skin, or regional lymph nodes. With a median follow-up duration of 11.6 years (range, 4.8 to 22.6 years), the local-regional control rate was 81%. No statistically significant differences in the pattern of failure were observed among the three studies.
Disease-Free and Overall Survival
Analyses of the probability of freedom from recurrence were performed on all 70 patients. The median duration of disease-free survival was 1.9 years. The 5- and 10-year disease-free survival rates were 34% and 32%, respectively. There was no statistically significant difference between the disease-free survival curve for the 239 patients with stage IIIB disease and that for the 70 patients with regional stage IV disease ( Fig 5).
We compared the overall survival of patients with regional stage IV breast cancer with 1,531 patients with distant metastatic breast cancer who were treated with doxorubicin and cyclophosphamide at our institution.12 The clinical outcome of the patients with regional stage IV breast cancer was significantly superior to that of patients with chemotherapy-naïve metastatic breast cancer (Fig 6). We also compared the overall survival of patients with stage IV breast cancer with patients who had oligometastatic disease (one or two sites) ( Fig 6). The patients with oligometastatic disease also experienced worse outcomes than patients who presented with regional stage IV breast cancer. ( Fig 7).
Side Effects Myelosuppression was universal, but no treatment-related deaths occurred. The majority of patients reported nausea and vomiting. Alopecia was universal and rapidly reversible. Surgical complications were within the expected range. Skin changes after radiotherapy included minimal to moderate erythema, desquamation, and fibrosis.5,6,7
The results of this retrospective analysis demonstrate that systemic and regional therapy can be combined safely and without excessive toxicity in patients with LABC and supraclavicular lymph node involvement. Furthermore, the results also demonstrate that the majority of patients who present with LABC and ipsilateral supraclavicular lymph node involvement can be rendered disease-free initially. More important, with a median follow-up of 11.6 years and a maximum follow-up of 22.6 years, our results indicate that approximately 32% of these patients will remain alive and disease-free at 10 years. Finally, the overall and disease-free survival curves were not significantly different for these patients and the 239 patients with stage IIIB disease who were treated in the same three prospective trials. However, the overall survival curve is significantly better than that of patients with metastatic breast cancer who were treated with cyclophosphamide plus doxorubicin at our institution.12 The presence of supraclavicular lymph node involvement is considered a predecessor to distant metastases. In 1907, Halsted13 published a study of 44 patients with breast cancer who presented with histologically proven supraclavicular lymph node involvement; only two (5%) of 44 patients survived longer than 5 years. Haagensen14 achieved no 5-year clinical cures among patients with supraclavicular involvement and reported a 56% local recurrence rate in those patients after radical mastectomy. Until 1988, the AJCC classification system for breast cancer classified patients with supraclavicular lymph node involvement in the N3 (stage IIIB) subcategory.15 In 1988, those patient classifications were moved to the stage IV category because it was believed that their outcome was similar to that of patients with distant metastases. The 1997 AJCC Manual for Staging of Cancer (tumor-node-metastasis classification) placed patients with ipsilateral supraclavicular lymph node involvement at diagnosis in the M1/stage IV (distant metastasis) subgroup.2 Clinical classifications are used mainly to determine prognosis and facilitate selection of the most appropriate treatment. It is clear that with regional therapy alone, patients with supraclavicular metastases fare poorly; few, if any, survive 5 years. However, it is equally clear that combined-modality therapy, including systemic chemotherapy, hormonal therapy, or both can improve the prognosis of these patients considerably. The inclusion of patients with supraclavicular involvement in the distant metastasis (stage IV) category may provide a disservice, because this classification connotes incurability and therefore may lead to suboptimal therapy with palliative intent. In summary, infraclavicular and supraclavicular lymph nodes are part of a continuum in the regional lymph node drainage of the breast. Axillary lymph nodes levels 1, 2, and 3 and the infraclavicular and supraclavicular lymph nodes are not separated on the basis of functional differences. They are separated according to arbitrary anatomic boundaries and gradual worsening of prognoses when treatment consists of surgery alone, radiation therapy alone, or both without systemic chemotherapy and/or hormonal therapy. We strongly recommend aggressive treatment of patients with LABC who have ipsilateral supraclavicular lymph node involvement but no other evidence of distant metastases. Such treatment includes combined-modality therapy that consists of anthracycline-containing chemotherapy regimens, surgery, radiotherapy (including all sites of initial involvement), and hormonal therapy in women with estrogen receptor–positive tumors. Such treatment provides these patients with the maximum chance of long-term disease-free and overall survival. Furthermore, we propose removal of patients with LABC who have ipsilateral supraclavicular lymph node involvement at presentation from the stage IV category. These patients should once again be classified in the stage IIIB category of the AJCC classification; their prognosis with combined-modality therapy is similar to that of patients who are classified currently in the stage IIIB category, and it is completely different from that of patients with distant metastatic disease.
Supported in part by the Nylene Eckles Professorship in breast cancer research.
Presented at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, May 16-19, 1998. R.A.B. is a recipient of the 1998 American Society of Clinical Oncology Merit Award.
1. Valero V, Buzdar AU, Hortobagyi GN: Locally advanced breast cancer. The Oncologist 1: 8-17, 1996 2. American Joint Committee on Cancer: Manual for Staging of Cancer ( ed 5 ). Philadelphia, PA, Lippincott-Raven, 1997 3. Kiricuta IC, Willner J, Kolbl O, et al: The prognostic significance of the supraclavicular lymph node metastases in breast cancer patients. Int J Radiat Oncol Biol Phys 28: 387-393, 1993 4. Jackson SM: Carcinoma of the breast: The significance of supraclavicular lymph node metastases. Clin Radiol 17: 107-114, 1966[Medline] 5. Hortobagyi GN, Blumenschein GR, Spanos W, et al: Multimodal treatment of locoregionally advanced breast cancer. Cancer 51: 763-768, 1983[Medline] 6. Hortobagyi GN, Ames FC, Buzdar AU, et al: Management of stage III primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Cancer 62: 2507-2516, 1988[Medline] 7. Booser D, Frye D, Singletary S, et al: Response to induction chemotherapy for breast cancer: A prospective multimodality treatment program. Proc Am Soc Clin Oncol 11: 82, 1992 (abstr) 8. Buzdar AU, Singletary SE, Booser D, et al: Combined modality treatment of stage III and inflammatory breast cancer: M.D. Anderson Cancer Center experience. Surg Oncol Clin N Am 4: 715-734, 1995[Medline] 9. Cox MR, Sell E: Analysis of Binary Data ( ed 2 ). New York, NY, Chapman and Hall, 1989 10. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 11. Mantel N: Evaluation of survival data and two row rank order statistics arising in its consideration. Cancer Chemother Rep 50: 163-170, 1966[Medline] 12. Greenberg PA, Hortobagyi GN, Smith TL, et al: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14: 2197-2205, 1996[Abstract] 13. Halsted WS: The results of radical operations for the cure of cancer of the breast. Ann Surg 46: 1-5, 1907 14. Haagensen CD: Diseases of the Breast. Philadelphia, PA, WB Saunders, 1956 15. American Joint Committee on Cancer: Manual for Staging of Cancer ( ed 3 ). Philadelphia, PA, Lippincott, 1988 Submitted February 2, 2000; accepted September 14, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. Multivariate analysis was performed by a logistic regression model.
.05 was considered statistically significant. Data were analyzed using the Statistica (Statsoft, Tulsa, OK) or SAS (SAS Institute, Cary, NC) software. 
